Colorectal Cancer: From Pathophysiology to Novel Therapeutic Approaches 2.0

A special issue of Biomedicines (ISSN 2227-9059). This special issue belongs to the section "Cell Biology and Pathology".

Deadline for manuscript submissions: closed (31 March 2022) | Viewed by 22730

Special Issue Editor

Department of Diagnostics and Public Health, P.le L.A. Scuro, University of Verona, 37129 Verona, Italy
Interests: brain tumors; meningioma; glioma; colorectal cancer; prognostic markers; tumor budding; poorly differentiated clusters
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Colorectal cancer (CRC) is one of the most common malignancies worldwide. Therapeutic approaches vary according to tumor location (colonic or rectal) and pTNM stage, the latter representing a main prognostic factor. In view of the overall good prognosis of nonmetastatic CRC, adjuvant treatments are not recommended for patients with pTNM stage I tumors, and their use is controversial for those with in pTNM stage II tumors. However, 10%–­20% of these patients undergo disease progression and would have benefitted from adjuvant therapies.

The identification of patients with nonmetastatic CRC at a high risk of progression is a current research challenge. In this regard, studies using liquid biopsy or searching for histological and molecular factors associated with metastatization could provide relevant information.

In recent years, immune checkpoint inhibitors have shown promising results in the treatment of a subset of metastatic CRC with high microsatellite instability (MSI). MSI CRC show dense immune cell infiltration, which is induced by numerous neoantigens created by their high mutational burden (TMB) linked to a deficient mismatch repair system. However, whether MSI is an optimal marker to predict response to immune checkpoint inhibitors is still to be determined. In addition, it is unclear whether microsatellite-stable CRCs with high TMB may respond to these therapies.

The aim of this Special Issue is to provide new insights into the process of CRC metastatization and into molecular and histopathological factors that may guide the development of novel therapies for this tumor.

Prof. Dr. Valeria Barresi
Guest Editor

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Keywords

  • liquid biopsy
  • epithelial–mesenchymal transition
  • tumor budding
  • poorly differentiated clusters
  • tumor mutational burden
  • microsatellite instability
  • immune checkpoint inhibitors
  • tumor-infiltrating lymphocytes

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Published Papers (6 papers)

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Research

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20 pages, 2140 KiB  
Article
A Prediction Model for Tumor Recurrence in Stage II–III Colorectal Cancer Patients: From a Machine Learning Model to Genomic Profiling
by Po-Chuan Chen, Yu-Min Yeh, Bo-Wen Lin, Ren-Hao Chan, Pei-Fang Su, Yi-Chia Liu, Chung-Ta Lee, Shang-Hung Chen and Peng-Chan Lin
Biomedicines 2022, 10(2), 340; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines10020340 - 01 Feb 2022
Cited by 6 | Viewed by 2606
Abstract
Background: Colorectal cancer (CRC) is one of the most prevalent malignant diseases worldwide. Risk prediction for tumor recurrence is important for making effective treatment decisions and for the survival outcomes of patients with CRC after surgery. Herein, we aimed to explore a prediction [...] Read more.
Background: Colorectal cancer (CRC) is one of the most prevalent malignant diseases worldwide. Risk prediction for tumor recurrence is important for making effective treatment decisions and for the survival outcomes of patients with CRC after surgery. Herein, we aimed to explore a prediction algorithm and the risk factors for postoperative tumor recurrence using a machine learning (ML) approach with standardized pathology reports for patients with stage II and III CRC. Methods: Pertinent clinicopathological features were compiled from medical records and standardized pathology reports of patients with stage II and III CRC. Four ML models based on logistic regression (LR), random forest (RF), classification and regression decision trees (CARTs), and support vector machine (SVM) were applied for the development of the prediction algorithm. The area under the curve (AUC) of the ML models was determined in order to compare the prediction accuracy. Genomic studies were performed using a panel-targeted next-generation sequencing approach. Results: A total of 1073 patients who received curative intent surgery at the National Cheng Kung University Hospital between January 2004 and January 2019 were included. Based on conventional statistical methods, chemotherapy (p = 0.003), endophytic tumor configuration (p = 0.008), TNM stage III disease (p < 0.001), pT4 (p < 0.001), pN2 (p < 0.001), increased numbers of lymph node metastases (p < 0.001), higher lymph node ratios (LNR) (p < 0.001), lymphovascular invasion (p < 0.001), perineural invasion (p < 0.001), tumor budding (p = 0.004), and neoadjuvant chemoradiotherapy (p = 0.025) were found to be correlated with the tumor recurrence of patients with stage II–III CRC. While comparing the performance of different ML models for predicting cancer recurrence, the AUCs for LR, RF, CART, and SVM were found to be 0.678, 0.639, 0.593, and 0.581, respectively. The LR model had a better accuracy value of 0.87 and a specificity value of 1 in the testing set. Two prognostic factors, age and LNR, were selected by multivariable analysis and the four ML models. In terms of age, older patients received fewer cycles of chemotherapy and radiotherapy (p < 0.001). Right-sided colon tumors (p = 0.002), larger tumor sizes (p = 0.008) and tumor volumes (p = 0.049), TNM stage II disease (p < 0.001), and advanced pT3–4 stage diseases (p = 0.04) were found to be correlated with the older age of patients. However, pN2 diseases (p = 0.005), lymph node metastasis number (p = 0.001), LNR (p = 0.004), perineural invasion (p = 0.018), and overall survival rate (p < 0.001) were found to be decreased in older patients. Furthermore, PIK3CA and DNMT3A mutations (p = 0.032 and 0.039, respectively) were more frequently found in older patients with stage II–III CRC compared to their younger counterparts. Conclusions: This study demonstrated that ML models have a comparable predictive power for determining cancer recurrence in patients with stage II–III CRC after surgery. Advanced age and high LNR were significant risk factors for cancer recurrence, as determined by ML algorithms and multivariable analyses. Distinctive genomic profiles may contribute to discrete clinical behaviors and survival outcomes between patients of different age groups. Studies incorporating complete molecular and genomic profiles in cancer prediction models are beneficial for patients with stage II–III CRC. Full article
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15 pages, 2509 KiB  
Article
Core Circadian Clock Proteins as Biomarkers of Progression in Colorectal Cancer
by María I. Aroca-Siendones, Sara Moreno-SanJuan, Jose D. Puentes-Pardo, Michela Verbeni, Javier Arnedo, Julia Escudero-Feliu, María García-Costela, Adelina García-Robles, Ángel Carazo and Josefa León
Biomedicines 2021, 9(8), 967; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines9080967 - 06 Aug 2021
Cited by 7 | Viewed by 3039
Abstract
Colorectal cancer (CRC) is one of the most common tumours in developed countries. Although its incidence and mortality rates have decreased, its prognosis has not changed, and a high percentage of patients with CRC develop relapse (metachronous metastasis, MM, or local recurrence, LR) [...] Read more.
Colorectal cancer (CRC) is one of the most common tumours in developed countries. Although its incidence and mortality rates have decreased, its prognosis has not changed, and a high percentage of patients with CRC develop relapse (metachronous metastasis, MM, or local recurrence, LR) during their disease. The identification of these patients is very important for their correct management, but the lack of prognostic markers makes it difficult. Given the connection between circadian disruption and cancer development and progression, we aimed to analyse the prognostic significance of core circadian proteins in CRC. We measured the expression of PER1-3, CRY1-2, BMAL1 and NR1D2 in a cohort of CRC patients by immunohistochemistry (IHC) and analysed their prognostic potential in this disease. A low expression of PER2 and BMAL1 was significantly associated with metastasis at the moment of disease diagnosis, whereas a high expression of CRY1 appeared as an independent prognostic factor of MM development. A high expression of NR1D2 appeared as an independent prognostic factor of LR development after disease diagnosis. Moreover, patients with a low expression of BMAL1 and a high expression of CRY1 showed lower OS and DFS at five years. Although these markers need to be validated in larger and different ethnic cohorts, the simplicity of IHC makes these proteins candidates for personalizing CRC treatment. Full article
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15 pages, 2119 KiB  
Article
Primary Tumor Sidedness, RAS and BRAF Mutations and MSI Status as Prognostic Factors in Patients with Colorectal Liver Metastases Treated with Surgery and Thermal Ablation: Results from the Amsterdam Colorectal Liver Met Registry (AmCORE)
by Madelon Dijkstra, Sanne Nieuwenhuizen, Robbert S. Puijk, Florentine E. F. Timmer, Bart Geboers, Evelien A. C. Schouten, Jip Opperman, Hester J. Scheffer, Jan J. J. de Vries, Kathelijn S. Versteeg, Birgit I. Lissenberg-Witte, M. Petrousjka van den Tol and Martijn R. Meijerink
Biomedicines 2021, 9(8), 962; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines9080962 - 05 Aug 2021
Cited by 24 | Viewed by 3138
Abstract
The aim of this study was to assess primary tumor sidedness of colorectal cancer (CRC), rat sarcoma viral oncogene homolog (RAS) and v-raf murine sarcoma viral oncogene homolog B (BRAF) mutations and microsatellite instability (MSI) status as prognostic factors predicting complications, survival outcomes, [...] Read more.
The aim of this study was to assess primary tumor sidedness of colorectal cancer (CRC), rat sarcoma viral oncogene homolog (RAS) and v-raf murine sarcoma viral oncogene homolog B (BRAF) mutations and microsatellite instability (MSI) status as prognostic factors predicting complications, survival outcomes, and local tumor progression (LTP) following surgery and thermal ablation in patients with colorectal liver metastases (CRLM). This Amsterdam Colorectal Liver Met Registry (AmCORE) based study included 520 patients, 774 procedures, and 2101 tumors undergoing local treatment (resection and/or thermal ablation) from 2000 to 2021. Outcomes following local treatment were analyzed for primary tumor sidedness of CRC, RAS, and BRAF mutations and MSI status. The Kaplan–Meier method was used to estimate local tumor progression-free survival (LTPFS), local control (LC), distant progression-free survival (DPFS), and overall survival (OS). Uni- and multivariable analyses were performed based on Cox proportional hazards model. The chi-square test was used to analyze complications. Complications (p = 0.485), OS (p = 0.252), LTPFS (p = 0.939), and LC (p = 0.423) was not associated with tumor-sidedness. Compared to right-sided colon cancer (CC) (reference HR 1.000), DPFS was superior for left-sided CC and rectal cancer (p = 0.018) with an HR for left-sided CC of 0.742 (95% CI, 0.596–0.923) and for RC of 0.760 (95% CI, 0.597–0.966). Regarding RAS mutations, no significant difference was found in OS (p = 0.116). DPFS (p = 0.001), LTPFS (p = 0.039), and LC (p = 0.025) were significantly lower in the RAS mutation group. Though no difference in LTPFS was found between RAS wildtype and RAS mutated CRLM following resection (p = 0.532), LTPFS was worse for RAS mutated tumors compared to RAS wildtype following thermal ablation (p = 0.037). OS was significantly lower in the BRAF mutation group (p < 0.001) and in the MSI group (p < 0.001) following local treatment, while both did not affect DPFS, LTPFS, and LC. This AmCORE based study suggests the necessity of wider margins to reduce LTP rates in patients with RAS mutated CRLM, especially for thermal ablation. Upfront knowledge regarding molecular biomarkers may contribute to improved oncological outcomes. Full article
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12 pages, 932 KiB  
Article
Preoperative Short-Course Radiotherapy and Surgery versus Surgery Alone for Patients with Rectal Cancer: A Propensity Score-Matched Analysis at 18-Year Follow-Up
by Radoslaw Pach, Piotr Richter, Marek Sierzega, Natalia Papp and Antoni Szczepanik
Biomedicines 2021, 9(7), 725; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines9070725 - 24 Jun 2021
Cited by 2 | Viewed by 2155
Abstract
A significant problem for long-term rectal cancer survivors may be the late toxicity of radiotherapy. It creates the possible risk of developing second primary malignancy and a theoretical decrease in overall survival. This study aimed to assess the influence of short-course preoperative radiotherapy [...] Read more.
A significant problem for long-term rectal cancer survivors may be the late toxicity of radiotherapy. It creates the possible risk of developing second primary malignancy and a theoretical decrease in overall survival. This study aimed to assess the influence of short-course preoperative radiotherapy in patients with locally advanced rectal cancer on overall survival, local recurrence rate, and second malignancy at 18-year follow-up. The rectal cancer trial was conducted in a single tertiary center between February 1992 and June 2006. A total of 389 patients with locally advanced rectal cancer (cT2-cT4, cN0/+, cM0) were included in the study. Preoperative radiotherapy was conducted in 148 patients and 241 patients underwent surgery alone. The propensity-matched group consisted of 105 patients operated on after radiotherapy and 105 controls. The number of local recurrences was 7 (6.7%) in the preoperative radiotherapy group and 22 (21%) in the surgery alone group (p = 0.016). The 18-year survival analysis showed no survival benefit in the preoperative radiotherapy group (38% versus 48%, p = 0.107) but improved recurrence-free survival (81% versus 58%, p = 0.001). The preoperative short-course radiotherapy significantly decreases the risk of local recurrence in locally advanced rectal cancer and may improve recurrence-free survival without an increased risk of second primary malignancy. Full article
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Review

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23 pages, 822 KiB  
Review
Bacteria-Mediated Modulatory Strategies for Colorectal Cancer Treatment
by Anna-Lena Mueller, Aranka Brockmueller, Niusha Fahimi, Tahere Ghotbi, Sara Hashemi, Sadaf Sadri, Negar Khorshidi, Ajaikumar B. Kunnumakkara and Mehdi Shakibaei
Biomedicines 2022, 10(4), 832; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines10040832 - 01 Apr 2022
Cited by 4 | Viewed by 4060
Abstract
Colorectal cancer (CRC) is one of the most common tumors worldwide, with a higher rate of distant metastases than other malignancies and with regular occurrence of drug resistance. Therefore, scientists are forced to further develop novel and innovative therapeutic treatment strategies, whereby it [...] Read more.
Colorectal cancer (CRC) is one of the most common tumors worldwide, with a higher rate of distant metastases than other malignancies and with regular occurrence of drug resistance. Therefore, scientists are forced to further develop novel and innovative therapeutic treatment strategies, whereby it has been discovered microorganisms, albeit linked to CRC pathogenesis, are able to act as highly selective CRC treatment agents. Consequently, researchers are increasingly focusing on bacteriotherapy as a novel therapeutic strategy with less or no side effects compared to standard cancer treatment methods. With multiple successful trials making use of various bacteria-associated mechanisms, bacteriotherapy in cancer treatment is on its way to become a promising tool in CRC targeting therapy. In this study, we describe the anti-cancer effects of bacterial therapy focusing on the treatment of CRC as well as diverse modulatory mechanisms and techniques that bacteriotherapy offers such as bacterial-related biotherapeutics including peptides, toxins, bacteriocins or the use of bacterial carriers and underlying molecular processes to target colorectal tumors. Full article
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40 pages, 2433 KiB  
Review
Identifying Novel Actionable Targets in Colon Cancer
by Maria Grazia Cerrito and Emanuela Grassilli
Biomedicines 2021, 9(5), 579; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines9050579 - 20 May 2021
Cited by 10 | Viewed by 6684
Abstract
Colorectal cancer is the fourth cause of death from cancer worldwide, mainly due to the high incidence of drug-resistance toward classic chemotherapeutic and newly targeted drugs. In the last decade or so, the development of novel high-throughput approaches, both genome-wide and chemical, allowed [...] Read more.
Colorectal cancer is the fourth cause of death from cancer worldwide, mainly due to the high incidence of drug-resistance toward classic chemotherapeutic and newly targeted drugs. In the last decade or so, the development of novel high-throughput approaches, both genome-wide and chemical, allowed the identification of novel actionable targets and the development of the relative specific inhibitors to be used either to re-sensitize drug-resistant tumors (in combination with chemotherapy) or to be synthetic lethal for tumors with specific oncogenic mutations. Finally, high-throughput screening using FDA-approved libraries of “known” drugs uncovered new therapeutic applications of drugs (used alone or in combination) that have been in the clinic for decades for treating non-cancerous diseases (re-positioning or re-purposing approach). Thus, several novel actionable targets have been identified and some of them are already being tested in clinical trials, indicating that high-throughput approaches, especially those involving drug re-positioning, may lead in a near future to significant improvement of the therapy for colon cancer patients, especially in the context of a personalized approach, i.e., in defined subgroups of patients whose tumors carry certain mutations. Full article
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